What you should be alert for in the history

The ABCDE (asymmetry, border irregularity, color variegation, diameter larger than 6mm, and evolution of the lesion) system for describing and evaluating suspicious skin lesions is a pneumonic for both the clinician and patient to identify the characteristic features associated with melanoma. When eliciting a history from the patient, the focus should be on these features of the lesion and how they have changed over time. However, it is important to note that not all melanomas display the features associated with the ABCDE system.

The presence of inflammation can be determined by features such as itching, crusting, or bleeding. Some dermatologists will employ the "ugly duckling sign"; the association of a pigmented lesion that looks different from all of its neighbors. Most melanomas are asymptomatic. The most common symptom is itching.

Questions pertaining to sites of potential metastasis should also be evaluated, including vision changes, seizures, headaches, shortness of breath, hemoptysis, coughing, dyspnea, new back pain, changes in bowel habits or any other unusual or new symptoms (fevers, chills, night sweats, weight loss, loss of appetite).

Other portions of the history that make lesions more suspicious include a personal history of skin cancer, previous biopsies for suspicious lesions, sun exposure history, childhood sunburns and/or blistering sunburns, use of tanning salons/lamps, and a family history of melanoma, pancreatic cancer, or other familial syndromes. Patients with fair skin (Fitzpatrick type I) are more likely to develop melanoma than patients with darker skin (Fitzpatrick type VI).

Characteristic findings on physical examination

A complete skin evaluation should be performed looking for additional suspicious lesions (including scalp, subungual regions, genitals, and perineum) as well as documentation of benign-appearing lesions. All lymph node basins (cervical, clavicular, axillary, inguinal and epitrochlear and popliteal in the case of extremity melanomas) should be palpated for lymphadenopathy and the abdomen assessed for palpable masses (hepatosplenomegaly). Particular attention should be given to assessing the primary lesion for evidence of ulceration, satellite lesions and in-transit metastasis.

The ABCDE characteristics should be applied when evaluating lesions on physical examination. Dermoscopy serves as a useful adjunct and can increase the sensitivity of identifying melanomas (Figure 1). Characteristics that suggest malignancy on dermoscopy include the presence of pigmented networks, globules, dots, blue-grey veil, or streaks. In addition, changes in lesions over time can be better appreciated with serial images taken dermoscopically. Total cutaneous photography (TCP) can be used for comparison at subsequent follow-up examinations. Detection of thin malignant melanomas in a curable stage is enhanced by utilizing these baseline photographs. Currently TCP has evolved into a system involving digital photography-based mole mapping. Patients who are high risk with multiple nevi can use the photographs to assist in self-examinations. Feit et.al. reported an increase in the melanoma diagnosis rate with the use of this technique. Moreover, they reported that melanomas identified with the assistance of TCP are generally thin melanomas. However, there are barriers to the increased use of TCP including the cost, which tends not to be covered by insurances, having the photos available during physical examinations, and a medical-legal concern for the potential of these photographs to be used in malpractice suits.

Figure 1.

Dermoscopic view of a primary cutaneous melanoma

Reflectance confocal microscopy (RCM) is a novel adjunct to skin cancer diagnosis that uses near-infrared light to achieve visualization of the epidermis and dermis at a cellular level. It is a non-invasive technique and studies have shown a superior diagnostic yield than dermoscopy and a reduction of benign biopsies. However, it requires a prolonged learning curve to be used appropriately and takes a longer time to assess a cutaneous lesion than dermoscopy.

Diagnosis confirmation

Any lesion that has the ADCDE features, evidence of inflammation (itching, bleeding, crusting), or a patient with a personal or family history that increases the risk for the development of melanoma should be considered for biopsy.

Biopsy should be done to generate a full-thickness specimen, as melanoma is staged and treated based on depth of invasion. Excisional biopsy of the entire specimen with narrow margins provides the best specimen for diagnosis and treatment plan. Partial biopsies, whether punch or shave, may not be optimal but are frequently utilized in clinical practice. Any uncertainty in the biologic diagnosis with partial biopsies should prompt the clinician to repeat the biopsy.

Confirmation of diagnosis requires histopathologic evaluation (Figure 2) and is diagnosed rapidly, accurately, and reproducibly through routine pathology. Morphologic criteria such as asymmetry, lack of circumscription, pagetoid intraepidermal spread, presence of cytologic atypia, increased cellularity, absence of maturation, and dermal mitotic figures help to distinguish a benign melanocytic nevus from melanoma. Pathologic characteristics that should be reported include Breslow thickness (mm), histologic ulceration, dermal mitotic rate per mm, peripheral and deep margins, microsatellitosis, regression, tumor infiltrating lymphocytes (TIL), vertical growth phase, angiolymphatic invasion, neurotropism, histologic subtype, and pure desmoplasia. While Clark levels may be reported, they are no longer considered as being part of a standard histologic report.

Figure 2.

Histology of a melanoma (H&E). (Courtesy of Bryan E Anderson, MD)

A single pathologic characteristic does not differentiate a benign lesion from a melanoma. Therefore, pathologic reports will give evidence for and against the diagnosis of melanoma. Combining the pathologic and clinical characteristics can help determine how likely an ambiguous lesion is to be either benign or malignant.

The major pathologic subtypes of melanoma are superficial spreading, nodular, lentigo maligna, acral lentiginous, and amelanotic. Superficial spreading melanomas are the most common type and arise from a nevus. Nodular melanomas are the second most common type, lack a radial growth phase, can have a variable presentation and are the quickest growing subtype. Lentigo maligna melanomas (Figure 3) are less common, appear in sun-exposed areas (face), and progress to invasiveness slowly. Acral lentiginous melanomas occur on the palms or soles of the hands or feet (Figure 4) and can occur as subungual melanomas as well. These lesions tend to occur in dark-skinned individuals. Amelanotic melanomas (Figure 5) can pose a diagnostic challenge due to lack of pigmentation. Satellite lesions of melanoma typically occur juxtaposed to the region of the primary melanoma (Figure 6). Cutaneous metastatic disease can have many morphologies and can occur at many locations on the skin (Figure 7).

Figure 3.

Lentigo maligna pathology. (Courtesy of Bryan Anderson, MD)

Figure 4.

Large melanoma on the foot. Breslow 5.0 mm, with ulceration. Found to have a + sentinel node. (Courtesy of Bryan E. Anderson, MD)

Figure 5.

Ulcerated amelanotic melanoma. (Courtesy of Bryan Anderson, MD)

Figure 6.

Satellite lesions around primary melanoma.

Figure 7.

Metastatic melanoma to the skin (Courtesy of Bryan Anderson, MD)

Immunohistochemical markers that label melanoma include S-100, vimentin, tyrosinase, MART-1, and HMB-45. These markers aid in diagnosis but are also shared features in benign melanocytes and nevi.

Fluorescent in-situ hybridization (FISH) testing for chromosome 6p25, 6 centromere, chromosome 6q23, and chromosome 11q13 has been shown to help distinguish melanocytic nevi from melanoma and can predict an increased risk of metastasis. FISH is helpful when immunohistochemical markers do not give a definitive diagnosis. A consideration should be made for FISH testing or comparative genomic hybridization for equivocal lesions.

Palpable or suspicious adenopathy should be biopsied preoperatively with an ultrasound guided needle biopsy (fine needle aspirate). Excisional biopsy of the lymph node should be considered only if needle biopsy is inconclusive.

Features of the primary lesion that contribute to the T stage include tumor thickness, the presence of ulceration, and the presence of mitosis in lesions less than 1 mm thick (T1b). Number of lymph nodes involved determines the N stage, which is also subclassified regarding the presence of micrometastasis or macrometastasis. The M stage is classified according to the presence of metastasis and the location of metastasis (distant skin, lymph nodes, lung, visceral involvement, or elevated serum LDH).

Staging of disease is constantly being updated; please see the National Comprehensive Cancer Network website (www.NCCN.org) for the most up-to-date staging information.

The presence of mitosis (greater than or equal to 1/mm2) and/or ulceration in thin melanomas classifies these as T1b. This is significant, as the presence of mitosis and/or ulceration carries a worse survival, necessitating lymph node evaluation at the time of surgery.

Stage I and II melanomas are all node-negative melanomas with varying depth of invasion. Melanomas are classified as stage III if there is evidence of lymph node metastasis, whether it is gross or microscopic involvement. A patient is classified as having node positive disease even if only isolated tumor deposits or cells are found within the lymph node. Distant metastasis is classified as stage IV disease.

In summary, the diagnosis of melanoma is dependent on a combination of histologic and clinical characteristics, which will determine the plan of treatment.

Who is at Risk for Developing this Disease?

Melanoma has the fastest growing incidence of any cancer in the United States. It is the fifth most common cancer in men and sixth most common cancer in women. The lifetime risk of developing melanoma for people in the United States is 1 in 58 overall, with an even higher risk in Caucasians. In 2011, the melanoma incidence rate was 19.7 per 100,000, and the death rate was 2.7 per 100,000. Incidence rates are projected to increase for white males and females through 2019. Death rates are projected to remain stable.

Risk factors for melanoma include genetic and environmental causes, or a combination of the two. Phenotypic traits associated with melanoma include fair skin, light hair, and patients with red hair having the highest relative risk versus dark hair, freckles, and light eye color. Patients with albinism and xeroderma pigmentosum are at higher risk for developing melanoma, as are patients on chronic immunosuppressive medications (such as what would be needed post organ transplant).

Ultraviolet (UV) sun exposure is the most important and most potentially modifiable risk factor contributing to the development of melanoma. Patients with intermittent, intense exposure to the sun are at a higher risk than those with chronic, continuous exposure. A history of sunburns, specifically blistering sunburns in childhood and adulthood, should also be elicited, as risk may be doubled with these factors. Artificial UV exposure in tanning salons exposes people to a higher dose of UVA over a shorter time period compared to sun exposure. Significant exposure before the age of 35 significantly increases the risk of melanoma.

Chronic immunosuppression can also increase the risk of melanoma due to cancer, AIDS, or organ transplantation. Up to 8% of patients with a personal history of melanoma will be diagnosed with another melanoma and patients with a personal history of nonmelanoma skin cancer have a 4.28 relative risk of developing melanoma.

The risk of melanoma increases with age, especially in men. In addition, melanomas diagnosed in men older than 50 years of age tend to be thicker, faster growing, and of a nodular type.

A positive family history is a strong risk factor for the development of melanoma. As the number of first-degree relatives with melanoma increases, so does the risk of developing the disease. Patients with one first-degree relative with melanoma are 1.7 times more likely to develop the disease, whereas two first-degree relatives possess a nine times increase in risk. In addition, as patients with a positive family history grow older, the cumulative risk of melanoma also increases.

Genetic syndromes associated with melanoma include xeroderma pigmentosum; familial atypical multiple moles and melanoma (FAMMM) syndrome, which is associated with pancreatic cancer (CDN2A mutation); BRCA2 mutations, which are associated with familial breast and ovarian cancer; patients with a family history of albinism; and patients with a red hair and freckling phenotype in the family.

Congenital melanocytic nevi are a risk factor for the development of melanoma as well, with larger lesions having the highest risk. These lesions can be either followed closely or removed prophylactically. Melanoma that occurs within congenital melanocytic nevi usually develops before the age of 10, therefore prophylactic removal should be considered early in life.

Risk factors identified on physical examination include total number of common nevi and atypical nevi (variable pigmentation, irregular asymmetric outline, and indistinct border).

What is the Cause of the Disease?

Etiology

Pathophysiology

Melanocytes, located within the basal layer of the epidermis, produce melanin to absorb ultraviolet (UV) radiation and prevent further DNA damage through absorption of UV rays. UV-induced DNA damage is normally repaired by DNA repair mechanisms. Any errors within DNA repair mechanisms, whether through genetic mutations or amount of damage outnumbering repair, may lead to the formation of an invasive melanoma. Nodular melanomas likely contain an alternate etiology as suggested by a lack of radial growth phase, variable degree of pigmentation, and occurrence on any surface of the body.

Sun exposure and tanning salons are the primary source of UV radiation. Most skin damage is caused by UVB rays, although UVA radiation has also been implicated in causing melanoma.

Genetic mutations have been discovered in melanoma that has led to trials examining agents targeting these pathways for potential treatment. Activating mutations in BRAF, CDK4, and NRAS have been discovered. In addition, activating mutations in CKIT have been identified in patients with acral, mucosal, and chronically sun damaged areas.

Systemic Implications and Complications

Familial Atypical Multiple Moles and Melanoma (FAMMM; also known as the B-K mole syndrome)

FAMM is a genetic disorder caused by germline mutations in CDKN2A. It is inherited in an autosomal dominant manner, with incomplete penetrance. Diagnosis is confirmed through family history, when two or more first-degree relatives have multiple dysplastic nevi and a history of melanoma. Overall survival is not different from sporadic melanomas.

CDKN2A mutations are associated with pancreatic cancer and melanoma, and should be documented as part of the family history on all melanoma patients.

Families with a suspected diagnosis of FAMMM should undergo frequent skin examinations and genetic evaluation for CDKN2A mutation. In addition, patients with suspected FAMMM should be referred for genetic counseling or to a melanoma risk assessment program prior to testing. This allows patients an opportunity to make informed decisions regarding the outcome of the genetic test.

Xeroderma Pigmentosum (XP)

XP carries a 1000-fold increase risk for melanoma. Regular self-skin examination is recommended along with sun avoidance, and regular examinations with a dermatologist who specializes in XP.

BRCA2

Families with mutations in BRCA2, which carries a significant increase in breast and ovarian cancers, also carry a 2.6 fold increase risk for melanoma.

Chronic Immunosuppression

Chronic immunosuppression increases the risk of melanoma. AIDS, chronic lymphocytic leukemia, non-Hodgkins lymphoma, and patients who have undergone organ transplantation all have an increased risk due to immunosuppression secondary to the disease itself or to anti-rejection medications.

Treatment Options

Prevention

Sunscreen

Sun protection

Self-examination

Surgical

Wide local excision

Sentinel lymph node biopsy

Lymphadenectomy

Metastatectomy

Limb infusion/perfusion

Medical-Systemic

Chemotherapy

Immunotherapy

Medical-Topical

Imiquinod

Local ablation

Intralesional injection with BCG or IFN

Physical Modalities

External beam radiation

Optimal Therapeutic Approach for this Disease

Prevention

Reduction of exposure to both natural and artificial ultraviolet radiation is one modifiable risk factor that could lead to a decrease risk of melanoma. Patients should be advised to avoid sun exposure during the mid-day hours, use clothing protection such as hats with broad brims, and use sunscreen. Sunscreens with a sun protection factor of at least 25 are effective at reducing the risk of acute sunburn.

Counseling patients concerning the importance of frequent self-examinations may aid in early diagnosis of melanoma. Family members are encouraged to assist patients with self-examinations, particularly of the patient's back. There are no established time frames for self-examination, but the authors recommend monthly exams, especially for high-risk individuals.

Surgical

Wide Local Excision (WLE)

The treatment of choice of melanoma is WLE of the primary lesion. Surgical margin is determined by depth of invasion and location of lesion. Melanoma in situ is excised with a margin of 0.5-1 cm. Melanomas are classified based on depth of invasion as thin (less than 1mm), intermediate (1 to 4 mm), or thick (greater than 4 mm).

Thin melanomas are treated with a 1-cm margin of excision, intermediate with a 1-cm to 2-cm margin of excision (depending on the anatomic location of the lesion and functional result), and thick melanomas are treated with a 2-cm margin of excision. WLE of all melanomas should be done to the level of the fascia of the underlying muscle.

Based on the anatomic location, closure options include primary closure, the use of advancement flaps, skin grafts, or tissue flaps.

Sentinel Lymph Node Biopsy (SLNB)

SLNB is used as an adjunct to WLE for determining lymph node involvement, which is the single most important factor in determining overall survival for melanoma. SLNB evaluates the first lymph node receiving lymphatic drainage from the melanoma site for metastasis. Patients without metastasis to the sentinel lymph node (SLN) are spared complete lymphadenectomy, which carries a significantly higher morbidity than SLNB (10% versus 33% incidence of lymphedema). Patients with palpable lymphadenopathy are not candidates for SLNB and proceed directly to needle biopsy and if positive to lymphadenectomy.

All patients undergo lymphoscintigraphy to identify which nodal basins need to be evaluated with SLNB. Truncal melanomas could theoretically drain to either axilla or both inguinal lymph node basins, which would require a SLNB of each of these nodal basins. The primary tumor site is injected with 3ml of isosulfan blue just prior to excision (Figure 8), and also injected with radiotracer in nuclear radiology during lymphoscintigraphy. A gamma probe is used in conjunction with visual identification of blue dye to locate the SLN. Single-photon emission computed tomography (SPECT) can also be used as an adjunct to help identify the SLN and identify additional SLN, although it is not the routine practice of the authors to use SPECT. Anaphylactic reactions can occur with the isosulfan blue, but the reported incidence is very low.

Figure 8.

Isosulfan blue staining of sentinel lymph node.

SLNB is performed for lesions greater than 1 mm in thickness with clinically negative lymph nodes. SLNB is also performed for T1b lesions, defined as lesions less than 1-mm depth with other high-risk features including ulceration and/or mitosis of greater than or equal to 1 per mm2. Sentinel node should be discussed in these patients with thin melanoma and high risk features although there is not a consensus as to whether this is considered "standard operating procedure." Consideration is made for SLNB for lesions over 0.76-mm depth, lesions with positive deep margin after a shave biopsy, and the majority of subungual melanomas. Lesions that have undergone regression in general, do not warrant SLNB, based on regression alone.

Lymphadenectomy

The current standard of care is complete lymphadenectomy of the affected lymph node basin for patients with a positive SLNB or with palpable lymph nodes proven to harbor metastasis via ultrasound guided needle biopsy. Type of lymphadenectomy depends on the lymph node basin affected. We are awaiting the results of clinical trials including MSLT-2 to ultimately determine the impact of completion lymphadenectomy on regional recurrence and long-term outcomes.

Axillary lymphadenectomy involves removal of all lymph nodes within levels I, II, and III. Patients with involvement of the head and neck region undergo modified radical neck dissection.

For inguinal lymph node involvement, superficial groin dissection has been the standard of care in the past, with some surgeons opting for biopsy of the first deep lymph node within the femoral canal (Cloquet's node) intraoperatively. If Cloquet's node is positive, a deep groin dissection to remove lymphatics around the iliac chain may be carried out. While PET/CT scans are not sensitive for detecting microscopic nodal disease, PET/CT avidity of deep inguinal lymph nodes in the absence of distant disease would be treated with a deep groin dissection as well. If there are palpable superficial inguinal nodes, one should strongly consider a deep dissection. There are newer surgical techniques for lymphadenectomy including minimally invasive superficial inguinal node dissections and minimally invasive deep pelvic lymphadenectomy either laparoscopically or robotically.

The Multicenter Selective Lymphadenectomy Trial II (MSLT-II) is a phase III randomized trial currently underway evaluating the need for completion lymphadenectomy after a positive SLNB versus observation of the affected nodal basin with serial ultrasound evaluation. This trial has completed accrual and we are awaiting the results.

Metastatectomy

In order for resection of metastatic disease to add benefit to survival, all disease would need resection. Resection of metastatic lesions in the setting of widespread disease may be considered in hopes of cure or for palliation of symptoms. Metastatectomy is considered on a case-by-case basis and all factors should be considered prior to surgery, including extent of resection and morbidity of the procedure. Factors assessing the biology of disease are important to consider as well, as resection followed by a short interval to recurrence is not optimal. These factors include disease free interval, the presence of multiple metastases, and poor characteristics of the primary lesion. Overall, the risk of surgery should be weighed against the survival benefit in all patients being considered for metastastectomy. All of these patients should be discussed in a multidisciplinary setting.

Survival benefit has been shown in patients who underwent resection of metastases to the skin, lung, gastrointestinal tract, liver, and brain. Patients with solitary sites of disease and favorable tumor biology were resected in these studies and all authors recommend careful selection of these patients prior to considering resection of metastasis.

Isolated Limb Perfusion/Isolated Limb Infusion

In-transit metastasis is defined as metastasis that occurs within the lymphatic system between the primary site and the regional lymph node basin.

Isolated limb perfusion (ILP) involves the direct perfusion of a surgically isolated extremity with hyperthermic high-flow melphalan and/or tumor necrosis factor. This is performed in the operating room by isolating the femoral artery and vein, inserting catheters for chemotherapy delivery, and placing a tourniquet proximally to the catheters to isolate the blood supply to the extremity. Acid base balance of the limb is maintained through a membrane oxygenator. In ILP deep of superficial pelvic lymphadenectomy can be performed at the time of the procedure.

Isolated limb infusion (ILI) is less invasive than ILP by percutaneously placing perfusion catheters in the affected limb. Melphalan is also used for infusion. Because no membrane oxygenator is used, the treated limb is acidotic, hypoxic, and mildly hyperthermic. Response rates for ILI are slightly lower than that for ILP (64% overall response versus 79%).

There is no consensus on which patients with in-transit metastasis to use ILP or ILI. ILP allows for lymphadenectomy to be performed at the time of treatment, yet superficial groin dissections can also be performed at the time of ILI. Patients with co-morbidities would benefit more from the less involved ILI. Some advocate starting with ILI, and using ILP as salvage for in-transit recurrences. There is the possibility of performing multiple infusions if ILI is utilized as well.

Medical-Systemic

Adjuvant Immunotherapy for high risk Stage 2 and Stage 3 patients

Ajuvant Interferon

Interferon alpha 2b is an adjuvant treatment regimen for patients with stage IIb or stage III melanoma. Published systematic review and meta-analysis looking at interferon treatment demonstrates that it improves disease free survival and delays recurrences, with a small improvement in overall survival.

Interferon is given in high-dose form subcutaneously, five times a week for the first month, followed by three times a week for the following 48 weeks. That amounts to a yearlong treatment with injections multiple times a week for a small improvement in overall survival with side effects that include flu-like symptoms (fever, chills, headache, muscle aches) for the duration of the treatment. A study published in 2009 by Pectasides et al compared 1 month of IFN treatment compared with 1 year of treatment in a prospective study. There were no differences in the groups with regard to disease free survival and overall survival, suggesting that a shortened course may be just as beneficial. Additional studies are needed to confirm these findings, as a majority of the studies looking at IFN treatment use a year-long course.

Pegylated IFN is another treatment option for patients with regional node disease. It is given for 5 years and demonstrated a slightly improved recurrence-free survival compared with observation. Overall survival, however, was not affected and the improvement in recurrence-free survival diminishes with extended follow-up.

It is the authors practice to refer all patients with stage III disease to a medical oncologist specializing in melanoma for counseling regarding interferon treatment. This allows the patient to make an informed decision regarding benefit in treatment and side effect profile.

Adjuvant Anti-CTLA 4 Antibody Treatment

Human monoclonal anti-CTLA 4 antibody treatment has been evaluated in the treatment of patients with melanoma with high risk of recurrence. A recent phase III randomized trial showed that ipilimumab improved overall survival in melanoma, with 1- and 2-year survival rates of 39% and 24%, respectively. Ipilimumab has also been approved by the FDA for treatment of metastatic melanoma.

The most common adverse events related to ipilimumab treatment were immune related events, including hepatitis, colitis, dermatitis, thyroiditis, hypophysitis, with the most common event being diarrhea. Other adverse events include injection site reaction, vitiligo, rash, anorexia, fatigue, pruritus, and leukocytosis.

Metastatic melanoma

PD-1 Inhibition

The newest and most exciting systemic agent is the PD-1 inhibitors. When comparing nivolumab to dacarbazine as 1st line therapy in patients with metastatic melanoma, 1-year survival rates were 73% versus 42%, with an objective response rate of 40% versus 14%. When comparing pembrolizumab to ipilimumab, there was an estimated 12-month survival rate of 74% and 68% with pembrolizumab every 2 weeks and 3 weeks respectively, and 58% for ipilimumab with decreased rates of treatment related adverse events in the pembrolizumab groups.

Anti-CTLA 4 Antibody Treatment

Human monoclonal anti-CTLA 4 antibody treatment has been evaluated in the treatment of patients with metastatic melanoma. A recent phase III randomized trial showed that ipilimumab improved overall survival in melanoma, with 1- and 2-year survival rates of 39% and 24%, respectively. Ipilimumab has been approved by the FDA for treatment of metastatic melanoma.

The most common adverse events related to ipilimumab treatment were immune related events, including hepatitis, colitis, dermatitis, thyroiditis, hypophysitis, with the most common event being diarrhea. Other adverse events include injection site reaction, vitiligo, rash, anorexia, fatigue, pruritus, and leukocytosis.

Although ipilimumab has been proven to be effective, with the advent of PD-1 and BRAF/MEK targeted therapy ipilimumab alone is no longer recommended as first-line monotherapy by the NCCN guidelines.

Combining Anti-PD1 and Anti-CTLA4 antibodies

Recently studies have demonstrated a benefit of treatment patients with combination ipilimumab with nivolumab. According to the CheckMate069 trial, overall survival rate at 2 years is 63.8% for combination therapy vs. 53.6% for monotherapy. This demonstrates a higher response rate than either drug alone. However, there are far more side effects. Further studies are ongoing looking at long-term outcomes with this regimen.

Targeted Therapy

BRAF Mutation

The discovery of activating mutations in the oncogene BRAF has led to studies evaluating BRAF inhibitors in the treatment of metastatic melanoma. Early clinical studies indicate that the majority of patients (approximately 70%) with metastatic melanoma carrying the BRAF V600E mutation will respond to BRAF inhibitor treatment. BRAF mutations are identified in approximately 50% of melanoma patients. Younger patients are more likely to be BRAF positive. One should consider molecular profiling for stage 4 melanoma patients for BRAF, NRAS and KIT mutations.

BRAF Inhibitors

Activating mutations in the BRAF gene have been shown to occur in melanoma, and agents with the ability to inhibit BRAF have recently been studied. A recent randomized, phase III prospective study compared patients with the BRAF V600E mutation with unresectable melanoma undergoing treatment with either vemurafenib (BRAF inhibitor) or dacarbazine. Response rates were 48% for vemurafenib and 5% for dacarbazine, with an overall 6-month survival of 84% for the vemurafenib group compared to 64% for the dacarbazine group.

The BRIM-3 trial compared the use of vemurafenib to dacarbazine and demonstrated an overall survival benefit in stage 4 patients of 13.6 months versus 9.7 months

Combining BRAF and MEK Inhibitors

There has also been shown a benefit of combination therapy with BRAF and MEK inhibition. In a study comparing vemurafenib and dabrafenib plus trametinib (a MEK inhibitor), overall response was 51% versus 64% with combination therapy. In another study overall response rates were 76% for combination therapy versus 54% for single agent dabrafenib. Unfortunately, patients tend to relapse after a median of 11-12 months due to acquired resistance to BRAF/MEK inhibition. A recent Phase II trial suggests that rechallenge with BRAF/MEK inhibitors after disease progression can achieve response after a resting period. Further randomized trials are needed to confirm these findings.

One of the major side effects of BRAF inhibitors is dermatologic. Patients on therapy should have baseline exams every 2 months as they are at increased risk of cutaneous squamous cell carcinomas.

Interleukin-2 (IL-2)

IL-2 stimulates natural killer cells, macrophages and B lymphocytes and had anti-tumoral activity. It is naturally secreted by CD4+ T lymphocytes and acts as a T-lymphocyte growth factor.

IL-2 can be considered for use in treatment of advanced or metastatic melanoma, preferably as part of a clinical trial. Reported response rates include complete response in 6% of patients and partial response rates of 10%. Overall objective response rate is reported as 17% in highly selected patients.

High dose IL-2 can either be given as a bolus or continuous dose. Toxicity can involve any organ system, mostly related to capillary leak leading to fluid extravasation and decreased perfusion. Patients considered for IL-2 treatment should be highly selected and treatment given in a center that specializes in the administration.

Side effects of IL-2 include flu-like symptoms, neutropenia, itching, anorexia, infection, dizziness and local injection site reactions.

Adoptive Cell Therapy (ACT)

ACT is a type of immunotherapy that involves harvesting the patient's own tumor infiltrating lymphocytes (TIL), growing them ex vivo, followed by infusion. TIL are harvested from the resected tumor specimen, then infused in conjunction with IL-2. Objective response rates from 49% to 72% have been observed using this therapy.

Chemotherapy

As immunotherapy has taken prominence in the initial treatment of melanoma, standard chemotherapy is used less commonlt. Historically, chemotherapeutic options for patients with metastatic melanoma include dacarbazine and temozolomide. Response rates have been reported from 10% to 20%, with median response duration of 3 to 4 months.

Dacarbazine in conjunction with cisplatin and vinblastine (CVD) and the Dartmouth regimen (dacarbazine, cisplatin, carmustine, and tamoxifen) have also been studied in patients with metastatic melanoma. There has not been any proven benefit of combination therapy over dacarbazine alone.

Carboplatin with or without paclitaxel has also been studied in patients with metastatic melanoma. Response rates up to 16% have been seen, but are reported as a short duration or response.

Biochemotherapy is the combination of cytotoxic therapy (dacarbazine, vinblastine, cisplatin, etc.) with immunotherapy (IL-2 and interferon, primarily). Clinical trials have demonstrated overall response rates of 21% to 64% but no increase in survival for patients with metastatic melanoma. Biochemotherapy should only be administered in institutions with ample experience in dealing with the associated adverse effects of these medications.

Medical-Topical

Topical therapies for melanoma include imiquimod, local ablation therapy, and intralesional injection with bacillus Calmette-Guerin (BCG) or interferon. These treatment options should not be used as first-line options, but may be considered in patients with positive margins after surgical resection, patients with in-transit metastasis, and in some cases of lentigo maligna. T-VEC (Tamilogene laherparepvec) injections for in-transit lesions uses a modified herpes simplex virus to induce cell lysis and to deliver granulocyte macrophage-colony stimulating factor (GM-CSF) directly into the tumor. It has shown an improved response rate as compared to only GM-CSF injections and has a bystander effect on other non-injected tumors.

External Beam Radiation

External beam radiation can be used in the treatment of melanoma to either improve loco-regional control of disease or assist in palliation of disease. Adjuvant radiation treatment to the primary excision site should be considered if surgical margins are not adequate due to the location of the lesion, such as the head and neck region. Definitive radiation treatment may be considered if surgical treatment is not possible.

Desmoplastic melanoma is a type of melanoma associated with extensive neurotropism. Increased local failure rates with excision of desmoplastic melanoma have been observed and radiation should be considered for these patients as well.

Patients with lymph node metastases are considered for radiation treatment if certain high-risk features are present on pathology. Multiple lymph nodes (more than three positive nodes), one or more nodes greater than 3 cm in size, extracapsular extension, or patients with recurrent disease after lymphadenectomy are considered for radiation treatment.

Improved regional control with radiation has been recently studied through a group in Australia. Overall survival was different between patients who received adjuvant radiation after lymphadenectomy versus those who did not. However, nodal basin recurrence was 16% for patients who received adjuvant radiation versus 26% for those who did not.

Palliative radiation treatments may be considered for distant subcutaneous and nodal metastases. Response rates of up to 79% have been observed, but overall survival has not been altered. There have been some newer papers evaluating the abscopal effect of radiation in the metastatic setting.

Stereotactic or whole brain irradiation can be used to treat brain metastases from melanoma to help prevent new symptomatic recurrences. Survival of patients with melanoma brain metastases treated with whole brain irradiation alone was poor, with reported 3.6- to 4.8-month survival. Other treatment options include surgical resection, stereotactic radiosurgery, and chemotherapy. Any of these treatment regimens may be used in conjunction with whole brain irradiation.

Patient Management

All patients diagnosed with melanoma should have annual skin examination and surveillance for life.

Guidelines for melanoma surveillance depend on stage of disease. Patients with stage I disease are recommended to have a complete history and physical exam, including whole skin surveillance and regional nodal evaluation, every 3 to 12 months for the first 5 years. Stage II patients should have follow-up every 3 to 6 months for the first 2 years, and every 3 to 12 months for 3 years after.

Routine imaging and routine laboratory evaluation is not recommended or currently supported for patients with treated melanoma, as detection of early recurrence has not been proven to change overall survival.

Surveillance physical exams should focus on the identification of local recurrence, lymph node metastasis, in-transit metastasis, satellite lesions, distant metastasis, and new primary lesions. Any systemic changes mentioned with the patient's history such as vision changes, headaches, or even changes in bowel habits may prompt further evaluation with imaging.

Prior to surgery for any recurrence or stage III disease, it is the general practice of the authors to obtain a whole body PET-CT scan and brain MRI to evaluate for evidence of additional metastases. We do not perform additional imaging on initial evaluation in patients with stage I or II disease.

Local recurrences are classified as either true scar recurrences or local recurrences. These are identified as subcutaneous nodularity or hyperpigmentation of the previous excision site or area on physical exam. True scar recurrences are defined as recurrences that contain an in situ or radial growth phase on pathology. Local recurrences are defined by the lack of an in situ or radial growth phase on pathology with deep dermal or subcutaneous fat recurrence within the melanoma scar or satellite lesions adjacent to the melanoma scar.

Treatment of true scar recurrences includes excision with appropriate margins according to tumor depth. SLNB could be considered in these cases as well, although currently there is no data to support SLNB for local recurrence.

Local recurrences, satellitosis, and in-transit disease are confirmed with biopsy if detected on physical exam. Treatment options consist of excision to clear margin, ILP or ILI, intralesional injection therapy, radiation, topical imiquimod, or enrollment into a clinical trial. Interferon alpha therapy for stage III disease is considered after local treatments if the patient is free of disease after treatment.

Lymph node metastases are confirmed with ultrasound guided fine needle aspiration for diagnosis, followed by regional lymphadenectomy if confirmed. Treatment adjuncts (which include external beam radiation and interferon treatment) are described in more detail above.

Recurrent lymph node metastasis after lymph node dissection is treated with re-excision if resectable. If the lesions are unresectable, systemic treatment may be offered. Radiation, immunotherapy, or chemotherapy is considered depending on extent of disease.

The presence of distant metastasis on follow up should prompt further imaging (PET/CT and MRI brain) to evaluate the entire body for metastasis and confirmation of metastasis with biopsy. Isolated distant metastasis may be considered for metastatectomy as mentioned previously.

Widespread metastases are treated with systemic chemotherapy, immunotherapy, or consideration for a clinical trial.

Unusual Clinical Scenarios to Consider in Patient Management

Melanoma in Pregnancy

The clinical course, prognosis, and overall survival of pregnant women with melanoma is similar to nonpregnant women. Thicker lesions are associated with pregnancy, likely due to delay in diagnosis and possibly response of the melanoma to systemic hormones. Prompt biopsy of suspicious lesions and WLE of confirmed melanoma is safe in pregnant patients. Biopsy and WLE should not be delayed until after delivery.

Lymphatic mapping with SLNB exposes the fetus to doses less than 5 mGy, well below the 50 mGy doses that lead to malformation. Isosulfan blue dye carries a 2% anaphylactic reaction risk after injection. Therefore it is recommended that pregnant women who require SLNB use radiocolloidalone, without the use of blue dye. Women in the third trimester of pregnancy may undergo WLE first, followed by SLNB after delivery.

Placental and fetal metastases from melanoma are rare, but are the most common types of cancer to metastasize to the placenta and fetus. Placental and fetal metastases from fetal metastases carry a poor prognosis, and pregnant patients with melanoma should be counseled regarding this route of transmission. In addition, the placenta is sent for histopathologic evaluation.

Patients desiring pregnancy after the diagnosis and treatment of melanoma should be counseled on a case-by-case basis. Because recurrence patterns in melanoma are fairly unpredictable, patients should be counseled on all the potential risks and informed on what treatment for recurrence could entail (chemotherapy, radiation). In general, patients at high risk for recurrence should wait five years after treatment and surveillance for pregnancy.

There is no associated increased risk of primary melanoma or recurrence with the use of oral contraceptives or hormone replacement therapy.

Subungual Melanoma

Subungual melanoma (Figure 9) arises within the nail bed and can represent a diagnostic challenge in differentiating it from a hematoma. Subungual melanoma is rare but has a higher incidence in dark-skinned individuals.

Figure 9.

Subungual melanoma.

Subungual melanomas are often diagnosed late, which leads to a poorer prognosis. This form of melanoma typically presents as discoloration of the nail, but up to 33% of subungual melanomas are amelanotic. One clue to the diagnosis is black pigmentation of the adjacent nail fold termed Hutchinson's sign. An ABCDEF system has been proposed for subungual melanoma; A for age (5th to 7th decade of life) and African-Americans, Asians, and Native Americans; B for brown to black, breadth of 3 mm or more and variegated borders; C for change in nail bed; D for digit most commonly involved; E for extension of pigment onto nail fold; F for family history of melanoma.

Because depth of invasion is difficult to assess on initial biopsies, the treatment of choice for these lesions is amputation to the middle interphalageal joint of the fingers or proximal to the distal joint of the thumb. Toe lesions are treated with amputation to the metatarsal-phalangeal joint and great toe lesions proximal to the interphalangeal joint.

SLNB is performed for all subungual melanomas unless palpable lymphadenopathy is present, in which case complete lymphadenectomy of the affected basin would be performed.

Desmoplastic Melanoma

Desmoplastic melanoma represents a variant of melanoma that had a tendency to invade nerves (desmoplastic neurotropic melanoma) and can pose a diagnostic challenge due to its tendency to occur as an amelanotic lesion. These lesions are frequently confused for scars, fibromas or even basal cell carcinoma. These features frequently lead to missed diagnosis, especially when they occur on mucosal surfaces (i.e., the lip).

Desmoplastic melanoma carries a higher incidence of local recurrence. Despite this, the incidence of distant and nodal metastasis is lower than for the typical melanoma. Although the incidence for metastasis is lower, the authors routinely perform SLNB for these patients.

Primary Dermal Melanoma

Primary dermal melanoma shows no evidence of epidermal involvement on biopsy. Because it is difficult to distinguish a primary lesion from a metastatic subcutaneous nodule, the authors routinely order PET/CT scans prior to treatment to rule out other sites of metastasis. If there is no evidence of distant disease, the lesion is treated as a primary lesion.

Melanoma Metastases from an Unknown Primary Site

Melanoma metastases that occur from an unknown primary site (Figure 7) have been estimated to occur in up to 9% of cases. The typical presentation occurs as a mass within a lymph node basin. Diagnosis is confirmed with fine needle aspiration biopsy or core needle biopsy of the mass.

Patients who present with an unknown primary melanoma need a thorough history and physical examination to determine if a patient had a missed diagnosis in the past (review all previous skin biopsy slides) or has a subtle skin lesion necessitating biopsy. An ultraviolet lamp (Wood's lamp) can be helpful in identifying a regressed primary melanoma by locating areas of depigmentation or halo nevi. Evaluation of the otolaryngologic, urogenital and ophthalmolic systems is also important to exclude unusual sites of primary melanoma.

Treatment includes lymphadenectomy of the affected nodal basin and/or resection of metastatic sites if isolated in selected patients. Patients are then considered for systemic and/or local adjuvant treatments (including radiation) as mentioned previously.

Overall survival in patients with an unknown primary melanoma is favorable compared to patients with a known primary site. Theoretically this is due to the patients host immune response (which potentially caused regression of the primary) allowing for a more favorable outcome.